individualized treatment of early breast...
TRANSCRIPT
INDIVIDUALIZED TREATMENT OF EARLY BREAST
CANCER
Ph.D. Thesis
Gyöngyi Kelemen, M.D.
Supervisor:
Prof. Zsuzsanna Kahán, M.D., Ph.D.
Department of Oncotherapy
Faculty of Medicine, University of Szeged
Szeged, Hungary
Szeged
2012
1
List of full papers that served as the basis of the Ph.D. thesis
I. Pálka I, Kelemen G, Ormándi K, Lázár G, Nyári T, Thurzó L, Kahán Z
Tumour characteristics in screen-detected and symptomatic breast cancers
Pathology & Oncology Research 14:(2) pp. 161-167. (2008)
IF: 1.260
II. Kelemen G, Farkas V, Debrah J, Ormándi K, Vörös A, Kaizer L, Varga Z, Lázár G,
Kahán Z.
The relation of multifocality and tumour burden with various tumour
characteristics and survival in early breast cancer
Neoplasma – submitted for publication
III. Kelemen G, Uhercsak G, Ormandi K, Eller J, Thurzo L, Kahan Z
Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-
paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer
Oncology 78:(3-4) pp. 271-273. (2010)
IF: 2.538
IV. Kelemen Gy, Varga Z, Lázár Gy, Thurzó L, Kahán Z
Cosmetic outcome 1-5 years after breast conservative surgery, irradiation and
systemic therapy
Pathology & Oncology Research – accepted for publication
IF: 1.483
Related articles
I. Varga Z, Cserhati A, Kelemen G, Boda K, Thurzo L, Kahan Z
The role of systemic therapy in the development of lung sequelae after conformal
radiotherapy in breast cancer patients
International Journal of Radiation Oncology Physics 80:(4) pp. 1109-1116. (2011)
IF: 4.503
2
II. Cserni G, Francz M, Kalman E, Kelemen G, Komjathy DC, Kovacs I, Kulka J,
Sarkadi L, Udvarhelyi N, Vass L, Voros A
Estrogen receptor negative and progesterone receptor positive breast carcinomas-
How frequent are they?
Pathology & Oncology Research 17(3):663-8. (2011)
IF:1.483
III. Dobi A, Kelemen G, Kaizer L, Weiczner R, Thurzo L, Kahan Z
Breast cancer under 40 years of age: Increasing number and worse prognosis
Pathology & Oncology Research 17:(2) pp. 425-428. (2011)
IF: 1.483
3
Table of contents
LIST OF ABBREVIATIONS .................................................................................................. 4
1. INTRODUCTION ............................................................................................................. 5
2. AIMS .................................................................................................................................. 6
3. PATIENTS AND METHODS .......................................................................................... 6
3.1 TUMOUR CHARACTERISTICS IN SCREEN-DETECTED AND SYMPTOMATIC BREAST CANCERS. . 6
3.2 THE RELATION OF MULTIFOCALITY AND TUMOUR BURDEN WITH VARIOUS TUMOUR
CHARACTERISTICS AND SURVIVAL IN EARLY BREAST CANCER ....................................................... .7
3.3 THE EFFECT OF THE MAMMOGRAPHIC APPEARANCE ON SURVIVAL IN PATIENTS WITH HIGH
RISK BREAST CANCER…………………………………………………………………………..9
3.4 COSMETIC OUTCOME 1-5 YEARS AFTER BREAST CONSERVATIVE SURGERY, IRRADIATION AND
SYSTEMIC THERAPY. ................................................................................................................. 10
4. RESULTS ......................................................................................................................... 12
4.1 TUMOUR CHARACTERISTICS IN SCREEN-DETECTED AND SYMPTOMATIC BREAST CANCERS 12
4.2 THE RELATION OF MULTIFOCALITY AND TUMOUR BURDEN WITH VARIOUS TUMOUR
CHARACTERISTICS AND SURVIVAL IN EARLY BREAST CANCER ...................................................... 16
4.3 THE EFFECT OF THE MAMMOGRAPHIC APPEARANCE ON SURVIVAL IN PATIENTS WITH HIGH
RISK BREAST CANCER ............................................................................................................... 29
4.4 COSMETIC OUTCOME 1-5 YEARS AFTER BREAST CONSERVATIVE SURGERY, IRRADIATION AND
SYSTEMIC THERAPY .................................................................................................................. 31
5. DISCUSSION .................................................................................................................. 41
6. SUMMARY, CONCLUSIONS ...................................................................................... 48
7. ACKNOWLEDGEMENTS ............................................................................................ 49
8. REFERENCES ................................................................................................................ 50
9. APPENDIX ...................................................................................................................... 58
4
List of abbreviations
ABD axillary lymph node dissection
ATC adriamycin (A)-paclitaxel (T)-cyclophosphamide (C)
BCSS breast cancer-specific survival
BS breast separation
CMF cyclophosphamide, methotrexate and fluorouracil
DCIS ductal carcinoma in situ
DDFS distant disease-free survival
ER oestrogen receptor
FISH fluorescence in situ hybridization
HER2 human epidermal growth factor receptor 2
IMRT intensity-modulated radiation therapy
LVI lymphovascular invasion
OAR organ at risk
OS overall survival
pT size of the largest invasive tumour focus
PTV planning target volume
PR progesterone receptor
RFS relapse-free survival
SNB sentinel lymph node biopsy
TOP2A topoisomerase2-alpha
5
1. Introduction
Breast carcinoma is a diverse disease entity, and the therapy should be based on specific
markers reflecting its individual biological behaviour [1-3]. The currently used prognostic
factors, however, do not reliably distinguish between true early breast cancers (usually screen-
detected and small, with a cure rate of around 95%), and those that exhibit an apparently low
TNM status, but in fact are at a more advanced stage with a high risk of relapse [3-6]. The
role of mammographic service screening in the reduction of breast cancer mortality has been
consistently revealed in numerous randomized controlled clinical studies and meta-analyses
[7-11]. Thus, breast cancer-related mortality is significantly reduced in women invited to
mammographic service screening as compared with those not invited to participate [7-11].
The type of mammographic image has recently been suggested as an independent prognostic
factor. The presence of casting-type calcifications has been demonstrated to be a prognostic
factor which carries a significantly higher risk of death as compared with cancers not
associated with this mammographic abnormality [2, 12-16]. In contrast, stellate lesions on the
mammogram reflect a more favourable prognosis than any other mammographic appearances
[2, 16-17]. The prognostic significance of multifocality/multicentricity and the tumour burden
have long been the subjects of investigation, but the results are inconclusive as the
nomenclature and methods applied were not uniform [1,18-23]. A larger tumour burden due
to multifocality has been related to poorer pathological characteristics [1, 18, 19], relapse-free
survival (RFS) [18, 23] and overall survival (OS) [18, 21, 22, 24]. In the case of multifocal
breast cancers, therefore, a consideration of the TNM stage alone, would lead to inaccurate
conclusions during treatment decision-making.
Breast-conserving surgery, usually followed by whole-breast irradiation, is the most
widely used surgical option for early breast cancer [25-29]. The cosmetic and the functional
outcome after postoperative breast radiotherapy depend on numerous patient- and therapy-
related factors. The radiogenic changes of the breast, such as dyspigmentation, teleangiectasia
or breast oedema, fibrosis causing breast swelling and tenderness, depend on the dose, the
irradiated volume and the individual radiosensitivity [30-33]. The impact of the systemic
therapy on the cosmetic outcome has been the subject of numerous studies [34-38].
6
2. Aims
2.1 We set out to prospectively investigate the patient- and tumour-related features in
early breast cancer shortly after the introduction of mammographic service-screening in
Hungary.
2.2 In an extended database, we aimed at the evaluation of how the multifocality and
calculated tumour burden in operable breast carcinomas relate to conventional pathological
and other tumour features, and the assessment of their effects on the outcome.
2.3 The aim of a retrospective analysis of a clinical study with adjuvant dose-dense
sequential adriamycin-paclitaxel-cyclophosphamide (ATC) chemotherapy was to investigate the
impact of the breast cancers’ mammographic appearance on survival in high risk breast cancer
cases.
2.4 In a retrospective cohort analysis, we intended to study the patient- and therapy related
factors that may influence the cosmetic and functional outcomes among our breast cancer
patients after breast-conserving surgery and conformal radiotherapy, with or without adjuvant
systemic therapy.
3. Patients and methods
3.1 Tumour characteristics in screen-detected and symptomatic breast cancers
Patients attending the Breast Unit of the University of Szeged, Hungary between May
1, 2004 and January 1, 2007 were eligible to take part in this study.
7
The following data were prospectively registered: the age of the patient at the time of
breast surgery, the type of breast surgery (breast-conserving surgery vs mastectomy), the
type of lymph node surgery (sentinel lymph node biopsy (SNB) vs axillary lymph node
dissection (ABD)), the pathological size of the largest invasive focus (pT), the histological
type, the histological grade, the hormone receptor (oestrogen receptor (ER) and progesterone
receptor (PR)) and human epidermal growth factor receptor 2 (HER2) status of the tumour
and the presence of lymphovascular invasion (LVI). The mode of detection of the
breast cancer was registered in the following categories: screen-detected (detected by breast
imaging within the national mammography screening program or by opportunistic
screening), symptomatic (detected via any symptom related to the tumour in a patient who did
not attend any screening program in the last two years) or interval cancer (the tumour was
diagnosed during the interval between two successive screening rounds and within 2
years after a negative screening finding). The mammographic appearance of the tumour,
based on the mammography report, was registered. Mammographic images were classified
according to Tabár et al. [12]. For the analysis of the association between the mammographic
image and other characteristics of the tumour, the previous categories were grouped in the
following way: spiculated lesions without calcifications, casting-type calcifications with or
without an associated tumour mass, and others.
Statistical analysis
For the categorical parameters, chi-square or Fisher tests were applied; for the analysis of
continuous data, variance analysis was used.
3.2 The relation of multifocality and tumour burden with various tumour characteristics
and survival in early breast cancer
Women attending the Breast Unit at the University of Szeged with invasive breast cancer in
clinical stage I or II between May 2004 and August 2010 were eligible for this study. All
patients underwent primary breast surgery, and adjuvant therapy was administered in
accordance with the national and international guidelines.
The data recorded were the age of the patient at the time of breast surgery, the mode of
detection of the breast cancer (mammography screening-detected, detected other than by
mammography screening or interval cancer) and its mammographic appearance. The
8
radiologic images were categorized as stellate (spiculated) tumour masses, circular tumours,
and parenchymal dystorsion/asymmetric density, while malignant microcalcifications were
categorized into two groups: casting-type calcifications and non-casting-type calcifications.
For the analysis of the association between the mammographic image and survival, these
categories were grouped as: stellate lesions without casting-type calcifications, casting-type
calcifications with or without an associated tumour mass and others. The type of breast
surgery (breast-conserving surgery vs. mastectomy), the type of lymph node surgery (SNB
vs. ABD with or without SNB), the pT, the histological type, the histological grade, the
presence of LVI and the information on lymph node involvement were also compiled. The
percentages of cells expressing the ER, the PR, Ki67 and topoisomerase2-alpha (TOP2A)
protein were routinely determined by means of immunohistochemistry [39]. A cut-off value
of ≥10% was used for ER or PR positivity, and >15% for TOP2A or Ki67 positivity. The
HER2 status was determined via immunohistochemistry and/or HER2 fluorescence in situ
hybridization (FISH) [39]. Immunohistochemistry data were not available for all patients.
Additionally, we retrospectively extracted the following data from the pathological reports:
the presence of multifocality, the sizes of the multiple foci (both invasive and in situ foci, if
present), and the grade of the in situ component, if present. Pathological reports were
considered only if there was a clear allusion to the presence or absence of more than one
tumour focus. In all cases, large-format histological sections (maximum size 60x90 mm) were
examined. The criterion of multifocality was the presence of more than one cancer focus
separated by non-malignant breast tissue. If two or more invasive foci were present, the
tumour was classified as invasive multifocal. Since most of the pathological reports did not
provide the extent of the breast parenchyma involved by malignant structures, the
pathological extent of the disease was estimated by summing the largest diameters of the
invasive and in situ cancer foci; this measure was taken as the tumour burden. In unifocal
cases, the tumour size comprised the tumour burden. Analyses were made on the basis of the
presence of multifocality, the magnitude of the tumour burden, other pathological features and
the survival data.
Survival data were collected on the basis of regular 6-month follow-up visits or events such as
relapse or death. RFS was defined as the time from breast surgery to any instance of disease
recurrence (local, regional or distant relapse or a contralateral breast cancer). Breast cancer-
9
specific survival (BCSS) was defined as the time from breast surgery to death due to breast
cancer. For the survival analyses, we excluded patients operated on after 2007. RFS and
BCSS were studied in relation to the patient and tumour characteristics; the median value (19
mm) of the tumour burden was applied as a cut-off value. In order to detect a difference in
outcome between the apparently early (cancers <15 mm) and more advanced cases as a
function of the studied variables, survival analysis was performed separately on a subgroup of
patients with breast cancers measuring <15 mm, regardless of whether they were unifocal or
multifocal.
Statistical analyses
For the categorical parameters, the chi-square test was applied; for the analysis of continuous
data, variance analysis and the Kruskal-Wallis test were used. The effects of the different
patient and pathological characteristics on the disease outcome were assessed with the
Kaplan-Meier method, and the effects of the various tumour-related factors on the disease
outcome were evaluated with the Cox proportional hazards model. Statistical analysis was
performed with SPSS 15.0 for Windows.
3.3 The effect of the mammographic appearance on survival in patients with high risk
breast cancer
Data of patients with high-risk breast cancer who received 4 cycles of adriamycin 60 mg/m2,
paclitaxel 200 mg/m2 and cyclophosphamide 800 mg/m
2 respectively, every 2 weeks were
prospectively collected.
RFS and OS were defined as the time from enrolment to any disease recurrence (local,
regional, distant relapse or contralateral breast cancer) or to death. After chemotherapy,
during the first 5 years of follow-up, patients had regular checkups every 6 months including
chest X-ray, abdominal ultrasound, blood tests, bilateral mammography and bone scan.
Statistical analyses
Kaplan-Meier survival analysis and the Breslow test were used.
10
3.4 Cosmetic outcome 1-5 years after breast conservative surgery, irradiation and systemic
therapy
Eligible patients had undergone unilateral breast-conserving surgery, with or without SNB
or/and ABD and conformal radiotherapy 1-5 years before the interview. Patients with prior
malignancy or any other significant health problem were excluded, as were those on
glucocorticoid therapy. The patients had been operated between May 2004 and December
2008, at either the Department of Surgery, University of Szeged, or at smaller surgical
departments.
Use of the following adjuvant medical therapies was permitted: a taxane-based postoperative
chemotherapy regimen (involving either docetaxel or paclitaxel at conventional doses)
completed 4 weeks prior to the radiotherapy (n=23, 13.1%); adjuvant hormone therapy with
either tamoxifen (20 mg/day) or an aromatase inhibitor (anastrozole, 1 mg/day, or letrozole,
2.5 mg/day), started 2 weeks before the initiation of radiotherapy (n=49, 24.7% and n=48,
24.2%, respectively); patients who did not receive any systemic medication during or after the
radiotherapy were also eligible for enrolment (n=75, 37.9%).
CT-based three-dimensional treatment planning and conformal radiotherapy were performed
in all cases with the patient in a supine position. All relevant technical details have been
published previously [40]. Briefly, CT images were acquired at 1 cm intervals throughout the
entire planning volume. The target volume and organs at risk (OARs) were contoured on the
CT slices in the radiotherapy planning system. The planning target volume (PTV) coverage
was analyzed via the dose-volume histograms and isodose visualization. Local or locoregional
radiotherapy was chosen according to the local protocol. The tumour bed boost was delivered
with either 6 MV photon or 8-15 MeV electron fields. The radiation dose to the remaining
breast parenchyma/chest wall and to the lymph nodes, if indicated, was 25x2 Gy (prescribed
to the mean of the PTV); a tumour bed boost of 5-8x2 Gy was delivered when necessary.
OAR constraints were used as previously described [40].
The following radiotherapy-related data were extracted from our database: the PTV, the
volume of the PTV that received more than 47.5 Gy, but less than 53.5 Gy (V95%–107%),
the overdosed volume of the PTV (V>107%), the volume and dose of the tumour bed boost,
11
the technique used and the breast separation (BS), i.e. the distance between the points at
which the tangential fields entered the body.
The cosmetic outcome was evaluated at a single routine 6-month check-up visit, 1-5 years
after the radiotherapy. The patients were examined, and a questionnaire relating to the
following items was completed: the overall cosmetic success in the opinions of the patient and
the physician (G. K. or Z. K.), the presence of breast fibrosis or oedema, teleangiectasia or
dyspigmentation, all scored on a 4-point categorical scale according to the modified system of
Johansen et al. [36, 41]. Briefly, the following scoring system was used. Breast fibrosis: 0:
none, 1: density slightly increased, 2: increased density and firmness, 3: very marked density
with retraction; Oedema: 0: none, 1: trace thickening of the skin, 2: marked oedema, leathery
skin texture, 3: severe oedema with papillary formation; Teleangiectasia: 0: none, 1: < 1 cm,
2: 1-4 cm, 3: >4 cm; Dyspigmentation: 0: none, 1: mild, 2: moderate, 3: severe. Physicians
classified the cosmetic result as excellent if no asymmetry or changes of the skin or the breast
contour occurred; in the case of slight, moderate or severe manifestation of at least one of
these factors, the outcome was considered good, fair or poor, respectively. The patients were
asked whether they felt pain or tenderness in the operated breast, and whether they had
experienced changes in their body image or in their clothing habits. The length of the excision
scar and the difference (regarded as measurable when ≥1.0 cm) in the jugulum-nipple distance
(indicative of breast asymmetry) were recorded. Data were additionally collected on smoking
habits, with the participants categorized as past or present smokers or non-smokers.
Statistical analyses
The various patient- and radiotherapy-related characteristics associated with the cosmetic and
functional outcomes were analyzed by the means of the chi-square test, analysis of variance
and logistic regression. The Kappa test was applied to investigate the connection between the
opinions of the physicians and the patients as concerns the cosmetic outcome. Binary
univariate logistic regression models were first utilized separately, followed by the
multivariate logistic regression model to examine joint effects and interactions. Statistical
analysis was performed with SPSS 15.0 for Windows.
12
4. Results
4.1 Tumour characteristics in screen-detected and symptomatic breast cancers
The data on 565 patients with 569 invasive breast cancers were collected. (Four patients had
synchronous bilateral invasive breast cancer.)
Patient- and tumour-related characteristics according to the mode of detection
Overall, 258 tumours (46%) were screen-detected, while 263 (46%) were symptomatic and
48 (8%) were interval cancers. The mean±SD age of the overall patient population at the
time of breast surgery was 58.1±10.9 years (range 27.8–85.1), while that of the cases with
screen-detected or symptomatic tumours was 58.4±7.6 and 58.5±13.9 years, respectively, and
that of the patients with interval cancers was 54.3±5.4 years (p=0.04). While 35.4% of the
patients with interval cancer, and 31% of the patients with symptomatic cancer were
premenopausal, only 20.2% of the patients with screen-detected cancer were
premenopausal (p=0.007). The pathological tumour characteristics are presented in Table 1.
Surgical and medical treatment options according to the mode of detection
The rate of breast-conserving surgery among the patients with screen-detected cancers was
significantly (p<0.001) higher than that in symptomatic or interval cancer cases.
Similarly, the rate of SNB was the highest in the group with screen-detected tumours
(p<0.001). In 15 clinically node-negative cases, no axillary surgery was performed because of
the advanced age of the patient. Adjuvant chemotherapy was significantly less frequently
applied in the patients with screen-detected cancers (36.8%) than in the symptomatic
(53.6%) or interval cancer (66.7%) cases (p<0.001). The frequency of use of hormone therapy
was similar in the three groups (Table 2).
Patient- and tumour-related characteristics according to the mammographic image
In two cases, no mammography had been performed prior to surgery, and in another three
cases, the result of the mammography was not available. Different characteristics according
to the mammographic image are presented in table 3. The cancers associated with casting-
type calcifications on the mammogram were significantly more often of ductal type (p=0.043,
Fisher’s exact test), of grade 3 (p<0.001), ER- and PR-negative (p<0.001) and HER2-positive
(p<0.001) than the cancers without casting calcifications. The mammographic images
revealed no differences in tumour size, lymph node status or LVI.
13
Screen-detected
(%)
Symptomatic (%) Interval cancer
(%)
p
Histological type
Invasive ductal
carcinoma
201/258 (78.2) 203/263 (77.2) 31/48 (64.6) 0.168 (chi-square test)
Invasive lobular
carcinoma
35/258 (13.6) 38/263 (14.4) 7/48 (14.6) 0.21 (Fisher’s exact test)
Others
(medullary,
mucinous,
tubular,
papillary)
22/258 (8.2) 22/263 (8.4) 10/48 (20.8)
Grade
1 75/257 (29.2) 26/260 (10.0) 8/48 (16.7) <0.001 (chi-square test)
2 115/257 (44.7) 124/260 (47.7) 22/48 (45.8)
3 67/257 (26.1) 110/260 (42.3) 18/48 (37.5)
Tumour size
1–10 mm 88/258 (34.1) 19/263 (7.2) 3/48 (6.2) <0.001 (chi-square test)
11–20 mm 120/258 (46.5) 93/263 (35.4) 24/48 (50)
>20 mm 50/258 (19.4) 151/263 (57.4) 21/48 (43.8)
Node
Negative 179/258 (69.4) 127/263 (48.3) 24/48 (50) <0.001 (chi-square test)
Positive 79/258 (30.6) 136/263 (51.7) 24/48 (50)
LVI
Negative 217/258 (84.1) 186/263 (70.7) 37/48 (77.1) 0.001 (chi-square test)
Positive 41/258 (15.9) 77/263 (29.3) 11/48 (22.9)
ER and PR
Positive 218/257 (84.8) 208/262 (79.4) 37/48 (77.1) 0.193 (chi square test)
Negative 39/257 (15.2) 54/262 (20.6) 11/48 (22.9)
HER2
Negative 222/255 (87.1) 220/262 (84.0) 38/48 (79.2) 0.310 (chi-square test)
Positive 33/255 (12.9) 42/262 (16.0) 10/48 (20.8)
Table 1 Pathological tumour characteristics for the various modes of detection
14
Screen-
detected n=258 (%)
Symptomatic n=263 (%)
Interval cancer n=48 (%)
p (chi-square
test)
Breast surgery
Breast-conserving
surgery
223 (86.4) 131 (49.8) 26 (54.2) <0.001
Mastectomy 35 (13.6) 132 (50.2) 22 (45.8)
Lymph node surgery
Sentinel node
biopsy
116 (45.0) 43 (16.3) 10 (20.8) <0.001
Axillary lymph node
dissection±sentinel
biopsy
137 (53.1) 210 (79.8) 38 (79.2)
No axillary
surgery
5 (1.9) 10 (3.9) 0 (0)
Adjuvant
chemotherapy
No 163 (63.2) 122 (46.4) 16 (33.3) <0.001
Yes 95 (36.8) 141 (53.6) 32 (66.7)
Adjuvant hormone
therapy
No 93 (36.1) 80 (30.4) 16 (33.3) 0.395
Yes 165 (63.9) 183 (69.6) 32 (66.7)
Table 2 Surgical and medical therapy following the various modes of detection of breast
cancer
15
Stellate lesions
without
calcifications (%)
Casting-type
calcifications ±
associated
tumour mass
(%)
Others (%) p
Histological
type
Invasive
ductal cancer
165/213 (77.5) 38/40 (95) 229/311 (73.5) 0.056 (chi-square test)
Invasive
lobular cancer
29/213 (13.6) 1/40 (2.5) 48/311 (15.4) 0.046 (Fisher’s exact
test)
Others
(medullary,
mucinous,
tubular,
papillary)
19/213 (8.9) 1/40 (2.5) 34/311 (10.1)
Grade
1 55/212 (25.9) 2/40 (5.0) 52/308 (16.9) <0.001 (chi-square test)
2 110/212 (51.9) 11/40 (27.5) 136/308 (44.2)
3 47/212 (22.2) 27/40 (67.5) 120/308 (38.9)
Tumour size
1-10 mm 42/213 (19.7) 8/40 (20.0) 59/311 (19.0) 0.098 (chi-square test)
11-20 mm 100/213 (47.0) 11/40 (27.5) 123/311 (39.5)
>20 mm 71/213 (33.3) 21/40 (52.5) 129/311 (41.5)
Node
Negative 123/213 (57.7) 19/40 (47.5) 185/311 (59.5) 0.350 (chi-square test)
Positive 90/213 (42.3) 21/40 (52.5) 126/311 (40.5)
LVI
Negative 168/213 (78.9) 27/40 (67.5) 241/311 (77.5) 0.287 (chi-square test)
Positive 45/213 (21.1) 13/40 (32.5) 70/311 (22.5)
ER and PR
Positive 189/212 (89.1) 23/40 (42.5) 247/310 (79.7) <0.001 (chi-square test)
Negative 23/212 (10.9) 17/40 (57.5) 63/310 (20.3)
HER2
Negative 198/212 (93.4) 18/40 (45.0) 259/308 (84.1) <0.001 (chi-square test)
Positive 14/212 (6.6) 22/40 (55.0) 49/308 (15.9)
Table 3 Comparison of the pathological tumour characteristics with the mammographic
image
16
4.2 The relation of multifocality and tumour burden with various tumour characteristics
and survival in early breast cancer
Among a total of 1234 breast carcinoma cases, 1071 were eligible for the analysis. The
mean±SD age was 58.6±12.0 (range 24.5-88.6) years. The patient and tumour characteristics
are presented in Tables 4 and 5. Around 40% of the cases were screen-detected. Among the
796 (74.3%) unifocal and 275 (25.7%) multifocal cancers found, there were 101 multifocal
invasive tumours, while in 174 cases a single invasive focus was associated with one or more
in situ foci.
The connection of multifocality with different tumour features
Multifocal cancers were more susceptible to screen detection, HER2 positivity and casting
calcifications in the mammogram than were unifocal cancers. Invasive multifocality was more
strongly associated than non-invasive multifocality with mastectomy (44% vs. 28%, p<0.01),
lymph node positivity (47 vs. 35%, p=0.03) and HER2 positivity (17 vs. 9%, p=0.02). The
maximum diameter of unifocal cancers was greater than the largest tumour focus in multifocal
cancers (p<0.001).
The connection between the tumour burden and different patient and tumour characteristics
The calculated mean±SE tumour burden in the unifocal and the multifocal cases was 19.5±0.4
and 31.2±0.9, respectively (p<0.001). We analyzed the standard pathological parameters
according to the tumour burden, using the median value of 19.0 mm as a threshold (Table 6).
The presence of lymph node metastases (p<0.001) or LVI (p<0.001) was associated with a
larger tumour burden. The mean±SE tumour burden was 21.7±0.4 vs. 28.9±1.4 mm in
invasive ductal vs. lobular carcinomas, respectively (p<0.01). A larger invasive tumour focus
and a larger tumour burden predisposed to ER, PR negativity (p<0.001) and HER2 positivity
(p<0.001). In multivariate analysis, only the connections between the tumour burden and ER,
PR negativity and HER2 positivity remained significant (p<0.001). A larger tumour burden
was associated with Ki67 positivity (p=0.02). A tumour burden larger than the cut-off value
was related to multifocality (p<0.001). The mean±SE tumour burden was 32.6±0.2 mm in
cases where there were casting calcifications in the mammogram, and 20.9±0.6 mm when the
lesion was categorized as a spiculated mass (p<0.001).
17
Variable Unifocal
cancers
(n=796)
(%)
Multifocal
cancers
(n=275)
(%)
p All
(n=1071)
(%)
Age (mean±SD) 58.7±12.2 58.5±11.5 0.87 58.6±12.0
Mode of
detection
Screen-detected
Symptomatic+interval
312 (39.2)
484 (60.8)
130 (47.3)
145 (52.7)
0.02 442 (41.3)
629 (58.7)
Mammographic
appearance
Stellate
Casting-type
Calcification±tumour mass
Other
308 (39.1)
35 (4.4)
444 (56.4)
78 (28.4)
51 (18.5)
146(53.1)
<0.001 386 (36.3)
86 (8.1)
590 (55.6)
Breast surgery
Excision
Mastectomy
570 (71.6)
226 (28.4)
186 (67.6)
89 (32.4)
0.22 756 (70.6)
315 (29.4)
Lymph node
surgery
Sentinel lymph node biopsy
or nothing
Axillary lymph node
dissection±sentinel lymph
node biopsy
382 (48.0)
414 (52.0)
139 (50.5)
136 (49.5)
0.48 382 (48.6)
414 (51.4)
Table 4 Patient-, tumour- and surgery-related parameters in unifocal and multifocal cancers
18
Variable Unifocal
cancers
(n=796) (%)
Multifocal
cancers
(n=275) (%)
p
(multifocal
versus
unifocal)
All
(n=1071)
(%)
Invasive
multifocal
cancers
(n=101) (%)
p
(invasive
multifocal
versus
unifocal)
All
(n=897)
(%)
Tumour size
(mean±SD) 19.5±10.8 16.3±9.6 <0.001 18.6±10.6 18.1±10.1 0.24 19.3±10.7
Lymph node
status
negative
positive
510 (64.1)
286 (35.9)
173 (62.9)
102 (37.1)
0.77 683 (63.8)
388 (36.2)
54 (53.5)
47 (46.5)
<0.05 564 (62.9)
333 (37.1)
Histological
type of the
invasive
component
Invasive ductal
carcinoma
Invasive lobular
carcinoma
Other
620 (77.9)
93 (11.7)
83 (10.4)
220 (80.0)
32 (11.6)
23 (8.4)
0.61 840 (78.4)
125 (11.7)
106 (9.9)
77 (76.2)
18 (17.8)
6 (5.9)
0.10 697 (77.7)
111 (12.4)
89 (9.9)
Grade
1
2 or 3
113 (14.3)
676 (85.7)
45(16.5)
228 (83.5)
0.38
n=1062
158 (14.9)
904 (85.1)
16 (16.2)
83 (83.8)
0.65
n=888
129 (14.5)
759 (85.5)
Presence of
DCIS
n=295 n=197 0.49 n=492 n=58 n=353
19
Grade 1
Grade 2
Grade 3
40 (13.6)
85 (28.8)
170 (57.6)
24 (12.2)
49 (24.9)
124 (62.9)
4 (13.0)
134 (27.2)
294 (59.8)
9 (15.5)
25 (43.1)
24 (41.4)
0.06 49 (13.9)
110 (31.2)
194 (55.0)
Presence of
LVI
LVI-
LVI+
648 (81.4)
148 (18.6)
224 (81.5)
51 (18.5)
1.00 872 (81.4)
199 (18.6)
88 (87.1)
13 (12.9)
0.17 736 (82.1)
161 (17.9)
ER status
ER+
ER-
606 (76.5)
186 (23.5)
198 (72.0)
77 (28.0)
0.14
n=1067
804 (75.4)
263 (24.6)
78 (77.2)
23 (22.8)
1.00
n=893
684 (76.6)
209 (23.4)
PR status
PR+
PR-
565 (70.9)
231 (29.1)
180 (65.5)
95 (34.5)
0.09
n=1069
743 (69.5)
326 (30.5)
70 (69.3)
31 (30.7)
0.73
n=895
633 (70.7)
262 (29.3)
Ki67 status
Ki67+
Ki67-
119 (40.8)
173 (59.2)
37 (52.9)
33 (47.1)
0.08
n=362
156 (43.1)
206 (56.9)
15 (51.7)
14 (48.3)
0.32
n=321
134 (41.7)
187 (58.3)
TOP2A status
TOP2A+
59 (26.6)
19 (31.1)
0.52
n=283
78 (27.6)
8 (32.0)
0.64
n=247
67 (27.1)
20
Table 5 Routinely assessed pathological parameters among unifocal, multifocal and invasive multifocal
TOP2A- 163 (73.4) 42 (68.9) 205 (72.4) 17 (68.0) 180 (72.9)
HER2 status
HER2+
HER2-
58 (7.4)
723 (92.6)
46 (17.2)
221 (82.8)
<0.001
n=1048
104 (9.9)
944 (90.1)
17 (17.3)
81 (82.7)
0.003
n=879
75 (8.5)
804 (91.5)
Triple
negativity
Yes
No
106 (13.4)
683 (86.6)
26 (9.5)
248 (90.5)
0.09
n=1063
132 (12.4)
931 (87.6)
7 (6.9)
94 (93.1)
0.08
n=890
113 (12.7)
777 (87.3)
21
Variable Tumour burden
≤19 mm (n=536)
Tumour burden
>19 mm (n=535) p
Tumour size
(mean±SD) 12.4±3.9 24.9±11.4 <0.001
Lymph node
status
negative
positive
383 (71.5)
153 (28.5)
300 (56.1)
235 (43.9)
<0.001
Histological
type
Invasive ductal
carcinoma
Invasive lobular
carcinoma
Other
437 (81.5)
46 (8.6)
53 (9.9)
403 (75.3)
79 (14.8)
53 (9.9)
0.01
Grade 1
2 or 3
118 (22.2)
411 (77.8)
40 (7.5)
490 (92.5)
<0.001
Presence of
DCIS
Grade 1
Grade 2
Grade 3
n= 219 (44.5% of
all)
44 (20.1)
69 (31.5)
106 (48.4)
n=273 (55.5% of
all)
20 (7.3)
65 (23.8)
188 (68.9)
<0.001
Presence of
LVI
LVI-
LVI+
460 (85.8)
76 (14.2)
412 (77.0)
123 (23.0)
<0.001
ER status
n=1067
ER+
ER-
436 (82.0)
96 (31.2)
368 (68.8)
167 (31.2)
<0.001
PR status
n=1069
PR+
PR-
403 (75.5)
131 (24.5)
340 (63.6)
195 (36.4)
<0.001
Ki67 status
n=362
Ki67+
Ki67-
76 (37.4)
127 (62.6)
80 (50.3)
79 (49.7)
0.02
22
TOP2A status
n=283
TOP2A+
TOP2A-
38 (24.7)
116(75.3)
40 (31.0)
89 (69.0)
0.29
HER2 status
n=1048
HER2+
HER2-
39 (7.4)
486 (92.6)
65 (12.4)
458 (87.6)
0.01
Multifocality
n=1071
Yes
No
60 (11.2)
476 (88.8)
215 (40.2)
320 (59.8)
<0.001
Table 6 Routinely assessed pathological parameters in 1071 breast cancers according to
tumour burden
23
Survival data
The median follow-up time for the population of 584 patients participating in the survival
analysis was 5.0 (range 0.3-7.3) years. There were 65 relapses (12.7%) and 30 deaths (5.8%).
The numbers of relapses and deaths in the multifocal vs. the unifocal cases were 17 vs. 48 and
7 vs. 23, respectively. The survival data did not differ as a function of the presence of
multifocality in the population. Among the conventional tumour characteristics, a larger
invasive tumour, the presence of LVI or lymph node involvement, HER2 positivity and triple
negativity were associated with a poorer RFS and OS (Table 7). The grade of the invasive
tumour was not related to the RFS. As regards the mode of detection, screen-detected tumours
gave RFS and OS statistics that were superior to those for non-screen-detected or interval
cancers. The mammographic appearance of the tumour was not related to the outcome. A
tumour burden >19 mm or >40 mm (extensive tumour) involved a shorter RFS and OS.
Neither multifocality nor invasive multifocality was associated with a shorter RFS or OS.
In Cox proportional hazards models, the pT, the lymph node status, triple negativity
and HER2 positivity remained independent determinants of an increased risk of relapse or
death (Tables 8 and 9).
24
Overall population (n=584)
RFS
estimated mean (±SE, years)
OS
estimated mean (±SE, years)
Largest invasive
tumour
<15 mm 7.0±0.1 7.3±0.0
≥15 mm 6.4±0.1 6.9±0.1
p (Mantel-Cox) <0.001 <0.001
Lymph node positivity
Yes 6.1±0.2 6.8±0.1
No 7.0±0.1 7.2±0.0
p (Mantel-Cox) <0.001 <0.001
Invasive tumour
grade
1 6.9±0.2 7.3*
2 or 3 6.6±0.1 6.9±0.6
p (Mantel-Cox) =0.17 =0.03
Presence of LVI
Yes 6.2±0.2 6.7±0.1
No 6.8±0.1 7.2±0.1
p (Mantel-Cox) =0.02 =0.004
HER2
Positive 5.7±0.4 6.3±0.2
Negative 6.7±0.1 7.1±0.1
p (Mantel-Cox) <0.001 <0.001
Triple negative
Yes 6.0±0.3 6.5 ±0.2
25
No 6.7±0.1 7.1±0.1
p (Mantel-Cox) =0.02 =0.002
Mode of detection
Screen-detected 6.9±0.1 7.2±0.1
Interval and non-
screen-detected cancer
6.4±0.1 6.9±0.1
p (Mantel-Cox) =0.001 =0.01
Mammographic
appearance
Spiculated tumour
mass without casting
calcification
6.7±0.1 7.1±0.1
Casting calcification ±
tumour mass
6.4±0.3 6.9±0.2
Other 6.7±0.1 7.1±0.1
p (Mantel-Cox) =0.66 =0.70
Multifocality
Yes 6.6±0.1 7.0±0.1
No 6.7±0.1 7.1±0.1
p (Mantel-Cox) =0.45 =0.59
Invasive multifocality
Yes 6.5±0.3 7.1±0.1
No 6.7±0.1 6.9±0.1
p (Mantel-Cox) =0.94 =0.70
Tumour burden
≤19 mm 6.7±0.1 7.1±0.1
>19 mm 6.5±0.1 6.9±0.1
p (Mantel-Cox) =0.09 =0.03
Tumour burden
<40 mm 6.7±0.1 7.1±0.1
26
≥40 mm 5.9±0.3 6.5±0.2
p (Mantel-Cox) =0.04 =0.02
*All cases are censored
Table 7 The effects of selected variables on disease outcome (median RFS and OS) among
the cases participating in the survival analysis
27
Variable Univariate
HR (95% CI)
p Multivariate
HR (95% CI) p
pT ≥15 vs. <15
mm
3.4 (1.8-6.5) <0.001 2.0 (1.0-4.0) 0.05
Lymph node-
positive vs. lymph
node-negative
3.8 (2.3-6.4) <0.001 3.0 (1.7-5.3) <0.001
Grade 2-3 vs.
grade 1 (invasive
component)
1.9 (0.8-4.7) 0.17
Presence of LVI 1.8 (1.1-2.9) 0.02 1.1 (0.6-1.7) 0.97
HER2 positivity 2.9 (1.7-5.3) <0.001 3.1 (1.7-5.8) <0.001
Triple negativity 1.8 (0.9-3.4) 0.06 2.2 (1.1-4.4) 0.02
Non-screen-
detected or
interval vs. screen-
detected
2.5 (1.4-4.3) <0.001 1.6 (0.9-2.8) 0.15
Casting
calcification vs.
spiculated tumour
mass
1.5 (0.6-3.8) 0.37
Spiculated tumour
mass vs. other
1.1 (0.7-1.9) 0.69
Presence of
multifocality
0.8 (0.5-1.4) 0.45
Tumour burden
>19 mm
1.5 (0.9-2.6) 0.09
Tumour burden
>40 mm
1.8 (1.1-3.4) 0.05 1.0 (0.5-2.0) 0.98
Table 8 The effects of selected patient- and tumour-related features on the risk of relapse
according to the Cox proportional hazards model: univariate and multivariate analysis
28
Category Univariate
HR (95% CI)
p Multivariate
HR (95% CI) p
pT ≥15 vs. <15 mm 8.9 (2.1-37.7) 0.03 2.5 (1.2-5.2) 0.03
Lymph node
positivity
5.0 (2.1-11.9) <0.001 3.3 (1.4-8.2) 0.01
Grade 2-3 vs. grade
1 (invasive
component)
25.2 (0.2-3012.88) 0.18
Presence of LVI 2.9 (1.3-6.1) 0.01 1.3 (0.6-3.0) 0.48
HER2 positivity 5.8 (2.6-12.7) <0.001 8.4 (3.2-22.1) <0.001
Triple negativity 3.5 (1.5-8.1) 0.003 6.8 (2.5-18.5) <0.001
Non-screen-detected
or interval vs.
screen-detected
3.7 (1.4-9.6) 0.01 2.3 (0.8-6.9) 0.13
Casting calcification
vs. spiculated
tumour mass
1.7 (0.5-6.4) 0.42
Spiculated tumour
mass vs. other
1.3 (0.5-3.0) 0.59
Presence of
multifocality
0.8 (0.3-1.9) 0.59
Tumour burden >19
mm
2.6 (1.1.-6.1) 0.03 0.8 (0.3-2.1) 0.65
Tumour burden >40
mm
2.6 (1.1-6.2) 0.03 0.9 (0.3-2.7) 0.94
Table 9 The effects of selected patient- and tumour-related features on the risk of death due to
breast cancer according to the Cox proportional hazards model: univariate and multivariate
analysis
29
4.3 The effect of the mammographic appearance on survival in patients with high risk
breast cancer
After a median follow-up time of 78.5 (64.3–100.0) months, 29 patients (52.7%) were free of
relapse, 34 patients (61.8%) were free of distant metastases, and 36 (65.5%) patients survived.
The median times of RFS, distant disease-free survival (DDFS) and OS were not yet reached
at 100.0 months. Two patients developed local relapse, 3 contralateral breast cancers and 21
distant metastases as follows: 3 lung, 3 bone, 2 liver, 1 brain and 1 pleural relapse; in 7, 3 and
1 cases metastases affected 2, 3 and 4 organs at the same time. Two other patients developed
second primary mesopharynx or colon cancer not rated as relapse.
The impact of the mammographic image on survival
The significant prognostic impact of the presence of casting-type calcifications on the
mammogram was still observed. Survival data, according to whether the tumour was or was
not associated with casting calcifications, are presented in table 10.
30
Casting
calcifications
Relapse-
free, n
Surviving
n
Median RFS
months
Median DDFS
months
Median OS
months
Present 1/12 6/12 11.5 11.5 29.6
Absent 28/43 30/43 >100 >100 >100
p 0.01 0.176 <0.001 <0.001 0.035
RFS = Relapse-free survival; DDFS = distant disease-free survival; OS = overall survival.
Table 10 Outcome according to the presence or absence of casting calcifications on the
mammogram
31
4.4 Cosmetic outcome 1-5 years after breast conservative surgery, irradiation and
systemic therapy
A total of 198 patients were enrolled in the study. The mean age of the population was
62.0±10.6 (range 25-89) years. The median follow-up time was 2.4 (range 1.2-5.9) years.
Most of the tumours measured ≤2.0 cm and were lymph node-negative (Table 11). Data
concerning the radiotherapy are presented in Table 12. One hundred and sixty-seven patients
(84.3%) received only breast irradiation, while 31 patients (15.7%) both breast and regional
lymph node irradiation. Twenty patients (10.1%) were treated with taxane-based
chemotherapy before the radiotherapy. The systemic therapy before the radiotherapy started
with an aromatase inhibitor or tamoxifen alone, in 49 (24.7%) and 48 (24.2%) cases,
respectively. Four (2.0%) and two (1.0%) patients received a taxane-based chemotherapy and
an aromatase inhibitor or tamoxifen thereafter, respectively. Seventy-five patients (37.9%) did
not participate in systemic therapy.
Factors influencing cosmetic outcome
The patients and the physicians considered the cosmetic outcome to be excellent or good in
76.3% and 47% of the cases, respectively; a weak correlation was observed between the
opinions of the physicians and the patients (Table 13).
A large majority of the patients (n=160, 80.8%) underwent their breast surgery at our
institute, and 127 (84.1%) of them regarded the cosmetic outcome as excellent or good more
often than did those who were operated on in smaller surgical departments (n=24/38, 63.2%)
(p=0.05). In the view of the physicians, the cosmetic outcome overall was less often excellent
or good as the tumour size increased: the mean±SD tumour size was 1.3±0.7 and 1.5±0.7 cm
in the excellent and good vs. the fair and poor outcome groups, respectively (p=0.015).
32
Among those patients who had an ABD, the physician considered the cosmetic outcome
excellent or good in 29 cases (37.7%), and fair or poor in 48 cases (62.3%, p=0.04). A
significant relation or interaction was not detected between these variables in the logistic
regression analysis. The incidence and severity of hyperpigmentation, fibrosis, oedema and
teleangiectasia are presented in Table 14.
33
Patient and tumour
characteristics
All
n (%)
Systemic therapy
n
Chemotherapy Tamoxifen Aromatase
inhibitor
Chemotherapy and
hormonal therapy
None
Menostatus
Premenopausal 48 (24.2) 12 22 0 4 10
Postmenopausal 150 (75.8) 8 26 49 2 65
Age
≤50 years 20 (10.1) 9 6 0 1 4
>50 years 178 (89.9) 11 42 49 5 71
Lymph node surgery*
Sentinel node biopsy
only
111 (56.0) 6 28 29 3 45
Axillary block
dissection
77 (38.9) 14 18 18 3 24
Tumour size
≤2.0 cm 164 (82.8) 12 41 41 3 67
>2.0 cm 34 (17.2) 8 8 7 3 8
34
Lymph node positivity
Lymph node-negative 155 (78.3) 8 38 38 1 70
Lymph node-positive 43 (21.7) 12 10 11 5 5
Tumour location
Upper quadrants 130 (65.6) 16 31 33 3 47
Central 34 (17.2) 1 7 11 1 14
Lower quadrants 34 (17.2) 3 10 5 2 14
Smoking habits
Never smoked 125 (63.1) 12 23 38 3 49
Current or previous
smoker
73 (36.9) 8 25 11 3 26
* Ten patients did not participate in lymph node surgery because of their advanced age
Table 11 Patient and tumour characteristics in the overall study population and according to the systemic therapy
35
Radiotherapy-
related data
All
mean±SD
(range)
Systemic therapy
mean±SD (range)
Chemotherapy Tamoxifen Aromatase
inhibitor
Chemotherapy
and hormonal
therapy
None
Volume of the
irradiated
breast (cm3)
1113.8±479.8
(218-3620)
1093.9±479.8
(404-2059)
974.7 ±447.9
(218-2217)
1140.5±413.5
(484-2358)
882.3 ±292.8
(547-1249)
1209.3±531.9
(425-3620)
V95%–107%
(%)
88.9±2.6
(81-95)
89.3±2.9
(84-95)
88.9±2.7
(81-94)
88.7±2.5
(82-94)
90.0±2.8
(86-94)
89.0± 2.4
(81-94)
V>107%
(%)
0.6±1.1
(0-6.9)
0.4±0.5
(0-1.9)
0.9±1.6
(0-6.9)
0.8±1.2
(0-4.5)
0.1±0.2
(0-0.5)
0.4±0.7
(0-4.1)
Boost volume
(cm3)
79.4±45.3
(13-258)
82.3±39.7 (32-
183)
73.7±43.2
(22-212)
72.6±37.7
(22-199)
69.2±36.5
(32-118)
88.4±53.6
(32-183)
Breast
separation
(cm)
21.7±2.7
(15.1-30.2)
21.6±2.6 (17.9-
25.7)
22.0±2.8
(16.8-30.2)
21.1±3.1
(15.1-30.1)
20.4±1.7
(18.1-22.5)
21.9±2.5
(16.4-28.9)
n (%) n
Boost 161 (81.3)
36
Photon boost 63 (39.1) 9 14 16 2 22
Electron
boost 98 (60.9) 11 25 26 3 33
10 Gy boost
dose 145 (90.1) 19 35 37 4 50
16 Gy boost
dose 16 (9.9) 1 4 5 1 5
Table 12 Radiotherapy-related data on the overall study population and according to the systemic therapy
37
Cosmetic outcome Excellent Good Fair Poor
Patient’s opinion (%) 93 (47.0) 58 (29.3) 44 (22.2) 3 (1.5)
Physician’s opinion (%) 32 (16.2) 61 (30.8) 68 (34.3) 37 (18.7)
Kappa 0.09 p<0.05
Table 13 Overall cosmetic outcome in the study population as assessed by the patient and the
physician. The patients’ subjective appreciation and the cosmetic result as classified by the
physician (the absence of any abnormality, or the slight, moderate or severe manifestation of
breast asymmetry or changes of the skin or the breast contour) are indicated.
38
Score 0 (%) Score 1 (%) Score 2 (%) Score 3 (%)
Hyperpigmentation 127 (64.1) 56 (28.3) 11 (5.6) 4 (2.0)
Fibrosis 131 (66.1) 37 (18.7) 30 (15.2) 0 (0.0)
Oedema 175 (88.4) 14 (7.1) 8 (4.0) 1 (0.5)
Teleangiectasia 176 (88.9) 3 (1.5) 6 (3) 13 (6.6)
Table 14 Incidence and severity of radiogenic changes of the skin, subcutaneous tissue and
breast parenchyma according to the modified scoring system of Johansen et al. [36, 41]
39
The effect of patient and tumour characteristics on cosmetic outcome
Thirty-one patients (19.7%) complained of pain in the operated breast, while 81 (40.9%)
reported tenderness. Breast tenderness occurred significantly more often among
premenopausal women or patients ≤50 years old (both p<0.05). The average±SD age of the
patients who complained or had no complaint of breast tenderness was 59.8±11.6 and
63.6±9.6 years, respectively (p<0.05). Breast fibrosis and/or oedema occurred in 67 (33.9%)
and 23 (11.6%) patients, respectively. Skin hyperpigmentation, found in altogether 71 patients
(35.9%) occurred in 59 (83.1%) of the patients >50 years old, and 12 (16.9%) of the women
≤50 years old, respectively (p<0.05), and its incidence decreased with the median time
elapsed after radiotherapy (2.1 and 2.5 years in the presence and the absence of
hyperpigmentation, respectively, p=0.02). Teleangiectasia developed in 22 patients (11.1%).
The mean±SD tumour size was 1.6±0.7 cm if moderate dyspigmentation occurred, and
1.3±0.7 cm in the other cases (p<0.05). The average±SD tumour size was 1.9±1.4 cm if breast
marked oedema occurred, and 1.4±0.7 cm in the other cases (p<0.05). Breast oedema
occurred in 15 (65.2%) and 8 (34.8%) among those patients who had or did not have ABD,
respectively (p=0.01). Breast oedema was related to dyspigmentation (p=0.003), fibrosis
(p<0.001) and breast asymmetry (p=0.032), whereas none of these abnormalities were
associated with teleangiectasia.
Changes in body image and clothing habits
Thirty-three (16.7%) patients mentioned changes in their clothing habits and 44 (22.3%) had
experienced a variation in their body image. Those patients who noticed body image changes
were younger than those who did not (the mean±SD age was 57.6±10.1 vs. 63.3±10.4 years,
respectively, p<0.005). Eighty-six percent of the postmenopausal, and 74% of the ≤50 years
old women needed to change their clothing habits (p<0.05), while this measure was 8.9% and
1.3% according to whether the patient received or did not receive systemic therapy,
respectively (p<0.005).
40
The length of the excisional scar and breast asymmetry
In most cases, the excisional scar was in the upper quadrants (n=130, 65.7%). The mean±SD
length of the scar was 8.2±3.5 (range, 3.0-28.0) cm. An average±SD breast asymmetry
(n=159) of 2.7±1.9 (range, 1.0-15.0) cm was found in 159 of the 194 evaluable patients
(nipple excision was performed in 4 patients). The average±SD extent of breast asymmetry
was 2.4±2.2 cm vs. 1.5±0.9 cm when the tumour was located in the upper vs. the lower
quadrants, respectively (p=0.05), and 2.1±1.7 cm vs. 2.9±2.9 cm when the tumour diameter
was ≤2 cm vs. >2 cm, respectively (p<0.05). The length of the scar did not influence any
attribute of the cosmetic outcome.
Radiotherapy and its effects on the cosmetic outcome
More severe dyspigmentation and breast oedema occurred in patients with larger PTVs
(p<0.001). The risk of more severe dyspigmentation and breast oedema increased by 18% and
23%, respectively, for every 100 cm3 increase in irradiated breast volume (OR=1.18, 95% CI:
1.07-1.31; OR=1.23, 95% CI: 1.12-1.36). Breast oedema was more frequent with increasing
BS (p<0.005), and was not related to nodal irradiation. The incidence of breast fibrosis was
significantly higher with larger PTVs (mean±SD value of PTV, patients with breast fibrosis:
1221.5±571.8 cm3 and patients without fibrosis: 1058.7±416.9 cm
3, p<0.05). The risk of
breast fibrosis increased by 7% for every 100 cm3 increase in irradiated breast volume
(OR=1.07, 95% CI: 1.00-1.14). No association was found between any of the attributes of
cosmesis and the dose inhomogeneity within the irradiated volume. The dose inhomogeneity
was related to the volume of the irradiated breast (p=0.037). The risk of V>107%≥1%
increased by 8% for every 100 cm3 increase in irradiated breast volume (OR=1.078, 95% CI:
1.003-1.158).
A higher boost volume favoured breast fibrosis and oedema (p<0.005 and p<0.001,
respectively). The risk of breast oedema and breast fibrosis increased by 21% and 12%,
respectively, for every 10 cm3 increase in boost volume (OR=1.21, 95% CI: 1.09-1.33 and
OR=1.12, 95%, CI: 1.03-1.12). Breast oedema and/or fibrosis was more frequent among those
patients who received a photon boost than those who received electrons (breast oedema: 13/63
41
vs. 4/98, p=0.001 and breast fibrosis: 26/63 vs. 26/98, p=0.038). No association was found
between the administration of systemic therapy and cosmetic or functional outcome.
Smoking habits and their effect on cosmetic outcome
One hundred and twenty-five (63.1%) patients had never smoked, 49 (24.7%) had smoked
previously and 24 patients (12.1%) smoked during the radiotherapy. Skin dyspigmentation
and teleangiectasia developed significantly less often among the patients who had never
smoked (both p<0.05).
5. Discussion
Mode of detection, mammographic appearance and multifocality as potential new prognostic
factors in early breast cancer
Our findings in both the smaller and the second, extended database, are in accordance with
those studies which demonstrated that the prognostic factors are more favourable in screen-
detected than in interval or symptomatic cancers. In numerous studies tumours were
obviously smaller, more probably lymph node-negative, [42-48] and better differentiated [44,
46-47] if screen-detected. Some groups have reported that cancers of a special histological
type, such as lobular or tubular carcinomas, are relatively more prevalent among screen-
detected tumours. [44, 46] In contrast, consistent with our data, no difference in histological
type was observed among the different groups in the study by Gill et al. [47] LVI was less
frequently present in screen-detected than in symptomatic cancers in that study. [47] We also
found that LVI was more prevalent in interval or symptomatic cancers than in screen-
detected cancers. It has been suggested previously that one indicator of the less aggressive
biological behaviour of screen-detected cancers is their higher hormone receptor content and
the less frequent expression of HER2. Whereas Gill et al. [47] and Klemi et al. [43] reported
that more screen-detected than symptomatic cancers were ER-positive, Joensuu et al. [46]
did not discern any difference in the expression of ER or HER2 between screen-detected and
symptomatic cancers. Similarly, we did not observe any difference in the ER, PR or HER2
status of the tumours as a function of the mode of detection.
42
Among screen-detected cancers, less radical surgical interventions were needed, and less
frequent chemotherapy was utilized, as a consequence of the earlier stage of these cancers.
However, the hormone therapy requirements did not differ between the groups as concerns
the mode of detection. This is a consequence of the similar distributions of the hormone
receptor-positive tumours in the different groups, and the frequent use of endocrine therapy
even in the early tumours, with the aim of the prevention of distant metastases, local relapses
or metachronous second breast cancers.
Interval cancers are detected from the symptoms in the interval between scheduled screening
episodes. A failure to detect breast cancer during screening depends on the testing procedure,
the interpretation by the radiologist, and the patient and tumour characteristics. A
biennial screening interval, a younger age [49-52] and increased breast density [52] favour
detection failure. More importantly, the nature of interval cancers may influence their
detection. Interval cancers have been demonstrated to occur more often in younger women,
and to exhibit a higher proliferation rate, a lower ER expression and higher HER2 expression
[49-52]. In our series, the interval cancers were significantly different from the screen-
detected cancers, and similar to the symptomatic cancers, as regards the tumour size, the
lymph node status, the presence of LVI and the grade, but the differences in histological type,
and ER/PR or HER2 status did not reach the level of statistical significance. This latter
inconsistency with the literature data may be explained by the relatively low number of cases
in our study. We found that a significant proportion of the interval cancers were
mammographically occult even at the time of diagnosis. These tumours belong among a
special subtype of interval cancers known as occult cancers [53].
Besides the classical prognostic factors (pT, lymph node status, grade, the presence or
absence of LVI, and the expressions of the hormone receptors and HER2), however, other
specific indicators for a better identification of the high-risk cases are needed. The
mammographic appearance of the cancer has recently been suggested as a prognostic factor
[2, 1-16, 54]. The risk of relapse or mortality in high-risk breast cancer patients was earlier
found to be about threefold if the tumour was associated with casting calcifications on the
mammogram [16]. In contrast, a highly favourable prognosis was experienced in small breast
cancers appearing as stellate lesions on the mammogram [2, 14]. We also analyzed the
potential role of mammographic image as a prognostic factor in a large database with a
43
relatively large proportion of very good prognosis and short follow-up time, and also in 55
high-risk breast cancer patients with a longer follow-up. The outcome of this latter analysis is
consistent with the literature data, and points to the long-persisting extreme difference in
prognosis between cases with or without casting calcifications on the mammogram. Our
observations underline that casting-type calcifications are not merely a marker of early
relapse, but a marker of a special biologic nature with very poor outcome.
The prognostic significance of multifocality and the tumour burden have been investigated by
many authors, but the results are inconclusive due to the different nomenclature used [1, 18-
23]. In general, multifocality is defined as the presence of two or more tumour foci separated
by normal breast parenchyma. Some studies have attempted to analyze the association
between the entire tumour burden and the outcome, by using the aggregate measure of the
dimensions or volumes of the tumour foci [20, 22, 58, 59]. These factors have been
demonstrated as determinants of poorer characteristics and outcome [1, 18, 19, 21-24]. This is
why we intended to study these tumour features for the characterisation of breast carcinomas.
In our extended database of operated early breast cancer patients, we found, that although
multifocal breast tumours (frequently screen-detected) are often smaller than unifocal breast
tumours, the aggregate size and hence the load of the cancer are larger, indicating a higher
risk of dissemination. The relatively high proportion of lymph node-positive cases in invasive
multifocal cancers reflects their aggressive behaviour and advanced stage. Although our
results do not support the role of multifocality as an independent predictor of a worse
prognosis, they should warn against the consideration of only a single tumour focus rather
than the whole extent of the disease if multiple cancer foci are present so as to avoid false
judgement.
In our study, multifocality and “invasive multifocality” occurred within the ranges reported by
other authors [22, 24, 55]. There are a number of reasons for the discrepancies between the
findings. Some authors do not distinguish between multicentric (situated in different
quadrants of the breast) and multifocal cancers [18], and include tumours with a single
invasive focus and in situ components [24], whereas others regard tumours as multifocal only
if more than one invasive focus is present [1, 19-22, 24, 56]. The strength of our study is that
we relied on data recorded in thorough examinations of large-format histopathology slides.
Nonetheless the retrospective nature of the study is a disadvantage.
44
The UICC/AJC TNM system is used as a prognostic tool, and the TNM stage has long served
as the basis of therapy decision-making. A major flaw is that, in cases of multifocality, the T
stage indicates the largest invasive focus of the disease, but ignores the effective tumour
burden, which may be significant if multiple foci are present. Our study accords with the
findings of others in that the TNM system in its current form is not suitable for these purposes
in the population of multifocal breast cancers [18, 21, 56, 58]. We found that, despite the
tumour being smaller, lymph node positivity was more prevalent among cancers containing
multiple invasive foci, and a larger aggregate tumour burden involved a poorer outcome.
These results are in accordance with those [18, 20, 22, 24, 58, 59] indicating that multifocality
is related to lymph node positivity. Moreover, Tot et al. found multifocal and diffuse lesion
distribution to be an independent predictor of breast cancer-related fatality [24]. In fact, the
diffuse distribution of the lesions is a rarely described phenomenon, and consequently its
effect should rather be analysed prospectively [57]. We could not recover this type of tumour
from the pathology records; such cases were probably classified as unifocal, which could play
a role in the incongruence between the findings of Tot et al. and ourselves [24].
For the estimation of tumour extent, we calculated the tumour burden by summing the largest
diameters of the tumour foci. This method provides merely an approximation; only exact
measurement of the entire tumour extent, encompassing the whole of the affected part of the
breast parenchyma, would furnish accurate information. For the estimation of tumour burden,
different approaches have been utilized in the literature. For assessment of the tumour burden
of multifocal cancers and the effect on survival, Rezo et al. used aggregate sizes and volumes
of the tumour foci, calculated as though they were spherical [22]. Interestingly, all measures
gave similar results: increasing tumour size predicted a poorer outcome after 60 months of
follow-up. Others followed the same method as we did, using the combined diameters of the
tumour foci [20, 56, 58].
The effect of multifocality on prognosis is controversial. Similarly to our findings, Cabioglu
et al. concluded that the presence of multiple invasive foci favoured lymph node positivity,
but the 55 month-survival did not differ between multifocal and unifocal cases [20].
Yersuhalmi et al. analysed a dataset on more than 25000 cases, and found that multifocality
carried a 17% extra risk of breast cancer-related death in stage I-III breast cancers [21]. In a
matched-pair analysis of 288 breast cancer cases, Weissenbacher et al likewise showed that
both the risk of relapse and that of death due to breast cancer were increased in multifocal
45
cancers [18]. Boyages et al. demonstrated a better 10-year survival rate among unifocal breast
cancer cases than among multifocal breast cancer cases, but this effect was restricted to
tumours >20 mm [56]. In a series of 574 breast cancer cases, Tot et al. observed a
significantly poorer BCSS rate in multifocal cancers, irrespective of whether only invasive or
invasive plus in situ multifocal cases were included [24]. We did not detect a difference in
survival between the cases with multifocal and unifocal breast cancers, but tumour size,
lymph node status and HER2-positive or triple negative status were independent predictors of
outcome. The relatively low overall number of events and short follow-up times could have
played a role in these results.
In Hungary, the national mammographic breast-screening program was introduced in 2001.
The quality indicators of the screening closely match the European guidelines, with the
exception of the participation rate, which is around 40%. However, the proportion of women
regularly screened for breast cancer is more than 60% as a result of the contribution of
opportunistic screening. Thus, in this mixed population of early breast cancer patients, the use
of tumour features such as the mode of detection and the mammographic appearance, the
multifocality of the tumour represent useful tools for individualized care.
Evaluation of the cosmetic and functional outcomes after breast-conserving surgery and
conformal radiotherapy, with or without adjuvant systemic therapy
The cosmetic and the functional outcome after the surgical and oncoradiological treatment
play an important role in the breast cancer patients’ quality of life. These factors depend on
many patient- and therapy-related characteristics. The age, the menopausal status, the weight
and the general health status of the patient, the stage of the tumour and the surgical
intervention clearly influence the results [30]. The radiogenic changes of the breast depend on
the irradiation’s features and the individual radiosensitivity [30-33]. Adjuvant chemotherapy
[41] and tamoxifen therapy [41, 76] have been suggested to predict a poor cosmetic outcome
[38].
More than three-quarters of the patients considered the cosmetic outcome to be excellent or
good, which is similar to the observations by other groups [36, 38, 60]. In contrast, in the
opinion of the physicians, only about half of the cases belonged in this category. One
explanation of the discrepancy might be the strict conditions used for the evaluation of the
46
cosmetic appearance. A further contributing factor could have been the relatively short
follow-up time in our study since the consideration of the radiation side-effects by the patient
may change in time [37].
The location and stage of the tumour clearly determine the cosmetic outcome [36, 60-64]. In
our study, breast oedema, fibrosis, teleangiectasia and dyspigmentation were all related to the
size of the tumour, and were interrelated. Similarly as in the studies by Johansen et al. and
Taylor et al., we found that tumours located in the upper quadrants and those with a larger
diameter were predisposed to more severe breast asymmetry [36, 60].
The available data are not completely unequivocal as regards the relation between a young
age and the cosmetic and functional outcomes. Most studies report an improved cosmetic
outcome among younger women [38, 60, 65, 66] though the opposite to has been suggested
[36]. We did not find any age-specific differences in the overall cosmetic outcome. However,
the different components of the cosmetic and functional results did depend on the age of the
patient. The more frequent breast tenderness or pain among ≤50 years old women might have
been related to hormonal effects and the change in body image in this age group could have
been dependent on psychological or mental factors. The higher incidence of dyspigmentation
in those over 50 years of age is probably due to the age-dependent response to radiation, with
an increased accumulation of melanin and lipofuscin, the pigments related to aging and
oxidative stress [67]. It is well known that radiogenic side-effects are more frequent for larger
breasts. Nevertheless, to the best of our knowledge, this analysis is the first to report cosmetic
results after conformal breast radiotherapy in relation to dose-volume data. Although
conformal radiotherapy was applied in the study by Lilla et al., a detailed analysis of the
radiotherapy-related data was not reported [66]. In that and other studies, the associations
between the side-effects and the irradiated volume were based on approximate data such as
the size of the breast or the bra cup [36, 41, 66, 68, 69] and the chest wall separation [68].
Likewise, dose homogeneity in the entire PTV was predicted after visualization of the dose
distribution at the central axis [64, 68] or was related to the use or avoidance of tissue
compensators or wedges [60, 70, 71]. In one of these studies, the dose homogeneity
demonstrated a parallel with the breast size [68], an effect confirmed by our results. In our
study, no association was detected between the dose inhomogeneity and poorer cosmesis as a
result of restricting the overdosed volume (V>107%) to 1% of the PTV, and the superposition
47
of individually weighted 6 or 15 MV segmental fields to the tangential fields [40]. Our
finding that the photon boost was more often related to breast oedema and fibrosis is in
accordance with the outcome of the robust analysis by Murphy et al. [69]. We consider that
this phenomenon is a consequence of the larger volume irradiated when 2 photon fields are
applied as compared with the use of one direct electron field. For the best cosmetic result, the
use of an electron boost is recommended, or the intensity-modulated radiation therapy
(IMRT) technique may be utilized [72-74].
Systemic therapy has been found detrimental to the cosmetic and functional outcome in many
studies [35, 41, 60, 64, 69, 75]. Most investigated the effects of chemotherapy with
cyclophosphamide, methotrexate and fluorouracil (CMF) or an antracycline-containing
regimen, either concurrently or sequentially with radiotherapy [36, 60, 75]. In the study by
Johansen et al., chemotherapy with CMF or with tamoxifen was associated with a 5-fold
(CMF) or 10-fold (tamoxifen) higher risk of breast fibrosis, respectively [36]. Taxane-based
combinations have become a routine option in adjuvant chemotherapy, but the effects of
sequentially applied taxane-based chemotherapy on breast cosmesis have not yet been
reported. We did not detect adverse effects of such a regimen, though the number of patients
was low. The third-generation aromatase inhibitors currently compromise the standard
endocrine therapy of postmenopausal women with hormone-dependent breast cancer.
However, tamoxifen is still administered in premenopausal and selected postmenopausal
women. Azria et al. demonstrated in their primal work that letrozole does not exert a
detrimental effect on early or late radiation skin toxicity [33]. In accordance with these
findings, aromatase inhibitor therapy in our analysis did not have any effect on the studied
parameters. In contrast, the prospective study by Azria et al. revealed that the concurrent
administration of tamoxifen with radiotherapy doubled the risk of subcutaneous fibrosis [31].
Likewise, we found that concomitant tamoxifen increased the risk of lung fibrosis
(OR=2.442) [40]. Due to the limitations of the analyses, other reports have not provided a
clear answer as to the effect of simultaneous tamoxifen therapy with radiotherapy on the
cosmetic outcome [41, 60, 61, 76]. Our survey suggested that tamoxifen therapy was related
to the change in body image, but since no specific radiogenic changes were detected, the
frequent weight gain associated with this medication may have played a role in this outcome
measure.
48
The patient and tumour characteristics influence significantly the cosmetic outcome; therapy-
related factors can also modify the breast aesthetics and the patient well-being. Although most
of the patients were satisfied with the cosmetic outcome, individual planning of the
oncoradiological therapy has considerable importance of reaching the best cosmetic result.
6. Summary, conclusions
6.1 Our findings reveal that screen-detected cancers have a more favourable
prognosis and need less oncological treatment than do tumours detected outside
mammographic service screening. The mammographic appearance of a tumour reflects its
biological behaviour, and should be considered when the management is to be optimized.
6.2 For the adequate management of breast cancer, an appropriate assessment of the
tumour distribution is essential; heightened attention is needed during the care of multifocal
breast cancers, which present in a more advanced stage than estimated from a he
consideration of only the largest focus.
6.3 Our results gave further evidence of the poorer prognosis of those tumours which show
casting-type calcification on the mammogram and highlight the importance of this special
type of tumour features.
6.4 The cosmetic outcome after breast-conserving surgery is primarily determined by the
stage of the disease and the consequences of radiotherapy. Despite the achievements made
regarding the effectiveness and side-effect profile of modern radiotherapy, a careful estimate
of its benefits remain necessary in each case and determination of the individual treatment
strategy accordingly.
49
7. Acknowledgements
I wish to express my special thanks to my supervisor Professor Zsuzsanna Kahán director of
the Department of Oncotherapy, University of Szeged for her support and scientific guidance
of my work.
I would like to thank Professor László Thurzó former director of the Department of
Oncotherapy, University of Szeged, who provided excellent working conditions for me at the
institute.
Special thanks are due to the staff members of the breast board: Professor György Lázár,
Attila Paszt, Zsolt Simonka, Katalin Ormándi, Csilla Hoffmann, Sándor Hamar, László
Kaizer, András Vörös, Erika Csörgő, Máté Lázár, without whom this task would never have
been fulfilled.
Special thanks are also due to Tibor Nyári, József Eller and Zoltán Varga for their guidance in
the statistical analysis.
I greatly appreciate all the support and work of high standard provided by physicians,
technicians and physicists of the Department of Oncotherapy, University of Szeged that
helped this dissertation to be born.
I would like to thank to my family and friends for encouraging and supporting me.
50
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